Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ocular toxicity of acetaminophen was investigated in cytochrome P450 inducer-responsive and nonresponsive strains of mice by light and electron microscopy. Acetaminophen injected into C57BL6 mice (responsive strain) that had been pretreated with beta-naphthoflavone produced cataract. The drug did not induce cataract in C57BL6 mice without the pretreatment or in DBA2 mice (nonresponsive strain) similarly pretreated with beta-naphthoflavone. Therefore, induction of cytochrome P450 enzymes that metabolically activate acetaminophen is essential for cataractogenesis. Following acetaminophen injection, tissue damage became noticeable first in the ciliary epithelium and then spread to the iris, corneal endothelium, and lens. The neural retina, retinal pigmented epithelium, and choroid remained unaffected. A close examination of tissues revealed that mitochondria are the primary target of acetaminophen cytotoxicity in ocular tissues affected. The nucleus, endoplasmic reticulum, and other subcellular structures appeared normal. The course of propagation of tissue damage and the almost exclusive damage to mitochondria suggest that the cytotoxic metabolite of acetaminophen is secreted with the aqueous humor by the ciliary epithelium and transported to the lens and that inhibition of mitochondrial energy metabolism, together with other effects of the metabolite, contributes to acetaminophen-induced cataract.
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PMID:Histocytological study on the possible mechanism of acetaminophen cataractogenesis in mouse eye. 894 Oct 46

Acetaminophen, or N-acetyl-p-aminophenol (APAP), is metabolized to N-acetyl-p-benzoquinone imine (NAPQI) by cytochrome P450 enzymes in the liver. The biotransformation of APAP is enhanced in P450-inducible C57BL6 (B6) mice but not in non-inducible DBA2 (D2) mice. Our previous studies showed that high doses of APAP administered to B6 mice pretreated with beta-naphthoflavone (BNF), a P450 inducer, produced ocular tissue damage but not in D2 mice similarly treated. We then proposed that the ocular toxicity of APAP is due to accumulation of its metabolite, NAPQI. In the present work, we tested this hypothesis by injecting NAPQI (50 microg in 2 microl propyleneglycol/eye) intracamerally into B6 and D2 mice. NAPQI produced cataract within a few hours (mean = 4 hr) both in B6 and D2 mice. Lower concentrations of NAPQI did not produce lens opacification. Injection of the solvent propyleneglycol only did not cause cataract. Thus, when NAPQI was injected, P450 inducibility was not essential for cataract formation. In addition to vacuole formation in the lens epithelial cells, alterations were observed in the corneal endothelium and ciliary epithelium. The retinal cell layers remained intact. Extensive mitochondrial damage and changes in chromatin structure in the nucleus were evident in the affected lens epithelial cells. The present result dissociates APAP ocular toxicity from its metabolic potentiation by P450 enzymes and will allow us to investigate the mechanism of cataractogenesis in in vitro lens culture systems.
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PMID:Cytotoxic metabolite of acetaminophen, N-acetyl-p-benzoquinone imine, produces cataract in DBA2 mice. 1060 76

The metabolic transformation of acetaminophen to N-acetyl-p-benzoquinone imine by cytochrome P450 enzymes (e.g., cytochrome P450 1A2) is a prerequisite for acetaminophen-induced cataract formation in mice. Aromatic hydrocarbons, such as beta-naphthoflavone, induce cytochrome P450 1A2 in C57BL6 mice via the mediation of the aromatic hydrocarbon receptor and render the animals susceptible to cataract formation by acetaminophen administration but not in DBA2 mice which do not respond to cytochrome P450 1A2 induction by these compounds. Polycyclic hydrocarbons, such as acenaphthylene, were recently found to induce cytochrome P450 1A2 gene expression in young DBA2 mice by aromatic hydrocarbon receptor-independent pathways. In this work, we investigated whether enhanced metabolism of acetaminophen to N-acetyl-p-benzoquinone by cytochrome P450 1A2 induction by acenaphthylene could produce cataract in young DBA2 mice. Fifteen-day-old DBA2 mice were pretreated with two intraperitoneal injections of acenaphthylene and, 24 hr later, with one injection of acetaminophen. In most mice, cataract developed 18-24 hr after acenaphthylene injection. Acenaphthylene treatment of young DBA2 mice resulted in a 2-fold increase in cytochrome P450 1A2-dependent methoxyresorufin O-demethylase activity in the liver. These results support the hypothesis that the aromatic hydrocarbon receptor-independent induction of cytochrome P450 1A2 enzyme leads to accumulation of sufficient N-acetyl-p-benzoquinone in the liver and cataract development in the eye.
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PMID:Acetaminophen produces cataract in DBA2 mice by Ah receptor-independent induction of CYP1A2. 1097 29